Sickle cell disease (SCD) is a genetic disease that afflicts over eighty thousand Americans, 4 to 5,000 newborns per year in the US, and 100s of thousands of children and adults world-wide. This disease arises from a single amino acid mutation of the beta globin chain of hemoglobin, which results in abnormal polymerization of deoxygenated hemoglobin. The deceptively simple biologic origin for SCD belies the debilitating chronic multi-faceted clinical syndrome with which it is associated; SCD is characterized by lifelong hemolysis, chronic anemia, recurrent painful vaso-occlusive crises (VOC), hepatic, renal, musculo-skeletal, and central nervous system complications, and a shortened life-expectancy. Our group has found an up to 33% incidence of pulmonary hypertension in adult patients with SCD who were screened and followed prospectively; with two-year follow-up, this pulmonary hypertension is associated with a 10-fold increased mortality rate.[unreadable] [unreadable] Hydroxyurea has emerged as a useful therapy in sickle cell disease. It is a cell-cycle specific agent that blocks DNA synthesis by inhibiting ribonucleotide reductase, the enzyme that converts ribonucleotides to deoxyribonucleotides. Hydroxyurea has been shown to induce the production of fetal hemoglobin (HbF) in patients with sickle cell anemia, with associated diminished morbidity and, likely, mortality in these patients. Any HbF is good in SCD, although it is estimated that levels of 20 percent HbF are required to substantially reduce the sickling propensity of red cells and to modulate disease severity. The majority of patients with SCD respond to hydroxyurea with a more than two-fold increase in HbF levels; in some patients the percent of HbF exceeds 10 or 15 percent, but it is not uniformly distributed in all cells, i.e. has a hetero-cellular rather than a pan-cellular distribution. The mechanism through which hydroxyurea augments fetal Hgb is incompletely characterized. An additional benefit of hydroxyurea may be through effects on the nitric oxide (NO) system. Recently, members of our group found that hydroxyurea therapy is associated with the intravascular and intra-erythrocytic generation of NO, and that NO increases HbF expression via the guanylyl cyclase/cGMP dependent pathways.[unreadable] [unreadable] We have treated more than 30 patients chronically with hydroxyurea to determine hematological changes Iongitudinally, and have established the maximal HbF raising effect of hydroxyurea in these patients. We have found that the levels of HbF that are induced by hydroxyurea alone are insufficient, and insufficiently widely distributed, to ameliorate the life-threatening complications of pulmonary HTN and of on-going hemolysis in patients with sickle cell disease.[unreadable] [unreadable] Earlier studies had suggested that the addition of erythropoietin (Erythropoietin) therapy to chronic hydroxyurea therapy may induce fetal hemoglobin at higher, more widely distributed, levels. We plan to test this in patients with sickle cell disease who have chronic kidney disease, which, presumably, leaves them with a depressed Erythropoietin reserve and an inability to tolerate standard doses of F-inducing therapy with hydroxyurea, and in patients with pulmonary HTN, which carries an ominous prognosis in SCD. A secondary endpoint of this study will be to evaluate if hydroxyurea plus Erythropoietin therapy can improve cardiovascular aerobic capacity in general, and in particular minimize symptoms and morbidity in patients with both chronic kidney disease and pulmonary HTN. We will enroll up to 60 males or females, age 18 and above with sickle cell disease. We began enrollment in June 2006 and have enrolled five subjects to date. Of those five subjects, 1 has completed the study, 1 was dropped due to a SAE, 1 was dropped due to non-compliance and 2 are still on going.[unreadable] [unreadable] We have recently amended the study to add Howard University as a participating site. This allows subjects to be recruited from Howard University. Screening and enrollment will take place at the NIH stie where EPO will be dispensed under our current IND. Subjects are followed weekly on this study. Three of these weekly visits per month may be performed at Howard University were interim tocicity checks, blood pressure measurements, and review of new symptoms will be performed.